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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 475-484

Carbohydrate Recognition Domain of Surfactant Protein D Mediates Interactions with Pneumocystis carinii Glycoprotein A

Zvezdana Vuk-Pavlovic, Joseph E. Standing, Erika C. Crouch, and Andrew H. Limper

Thoracic Diseases Research Unit, Division of Pulmonary, Critical Care, and Internal Medicine, and Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota; and Department of Pathology, Jewish Hospital at Washington University, St. Louis, Missouri

Pneumocystis carinii continues to cause severe pneumonia in immunocompromised patients. Surfactant protein D (SP-D), a lung collectin, markedly accumulates during P. carinii pneumonia and binds to glycoprotein A (gpA) on the surface of P. carinii, thereby enhancing interactions with alveolar macrophages. Herein, we report the structural basis of the interaction of SP-D with gpA. We demonstrate that natural SP-D binds to purified gpA in the presence of 2 mM calcium in a saturable, concentration-dependent manner, which is abolished by 10 mM ethylenediaminetetraacetic acid. Increasing concentrations of calcium under otherwise cation-free conditions significantly enhance SP-D binding to gpA, whereas manganese and magnesium cations have minimal effect. Maximal SP-D binding occurs at pH 7.4, with significant inhibition at pH 4. SP-D binding to gpA is also competitively inhibited by maltose>glucose>mannose>N-acetyl-glucosamine. Comparison of the binding of various natural and recombinant forms of SP-D to gpA reveals that the number of carbohydrate recognition domains (CRDs) in a given SP-D form determines the relative extent of binding to gpA. Maximal binding is observed with natural SP-D (dodecamers and higher order SP-D complexes) followed by recombinant dodecamers. In contrast, recombinant full-length trimers exhibit substantially less binding, which is similar to that observed with a recombinant truncated molecule consisting of the CRD and neck regions, and containing trimers of this portion of the molecule. Taken together, these findings strongly indicate that the CRD of SP-D mediates interaction with P. carinii gpA through its attached oligosaccharides and that the extent of SP-D binding to P. carinii is greatest with dodecamers and higher order forms of SP-D.

Abbreviations: bis-(sulfosuccinimidyl)-suberate, BS3; bovine serum albumin, BSA; complementary DNA, cDNA; carbohydrate recognition domain, CRD; ethylenediaminetetraacetic acid, EDTA; major surface glycoprotein A of P. carinii, gpA; isopropylthiogalactopyranoside, IPTG; lipopolysaccharide, LPS; recombinant dodecameric SP-D, rSP-D; recombinant truncated rat SP-D CRD molecule, rSP-D/CRD; full length trimeric SP-D mutant, rSP-D-ser15/20; standard deviation, SD; sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE; standard error of the mean, SEM; surfactant protein, SP; Tris-buffered saline, TBS.




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